(2S,3R)-2-amino-3-(3,4-dihydroxyphenyI)-3-hydroxypropanoic acid, also known as L-threo-dihydroxyphenylserine, L-threo-DOPS, L-DOPS or Droxidopa, is an orally active synthetic precursor of norepinephrine. Droxidopa replenishes depleted norepinephrine, allowing for re-uptake of norepinephrine into peripheral nervous system neurons. This reuptake, in turn, stimulates receptors for vasoconstriction, providing physiological improvement in symptomatic neurogenic orthostatic hypotension patients. It has also shown efficacy in other diseases, such as Parkinson's disease and depression.
Droxidopa has been used in Japan for many years for the treatment of orthostatic hypotension. It was originally approved in 1989 for the treatment of frozen gait or dizziness associated with Parkinson's disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy.
Marketing approval was later expanded to include treatment of vertigo, dizziness and weakness associated with orthostatic hypotension in hemodialysis patients.
Droxidopa has the following chemical structure:

Its chemical preparation generally involves a multi-step synthesis. Typically, one or more of the necessary steps in the synthesis require that reactive sites, other than the site targeted for the reaction, are temporarily protected. Thus, the synthesis of Droxidopa typically comprises at least one protecting and associated deprotecting step. For example, the catechol moiety, the amine moiety, and/or the carboxyl moiety may require protection and subsequent deprotection, depending upon the synthetic route and the reagents used in the preparation of Droxidopa.
Several synthetic and enzymatic approaches to Droxidopa have been described in the literature.
Most of them entail the coupling between a conveniently protected 3,4-dihydroxy benzaldehyde with glycine to yield a diastereomerically enriched mixture of threo-DOPS. This approach, described by Microbiochemical Research Foundation in patent EP 0112606 B1, is not stereoselective and relies on fractional crystallizations to separate a threo/erythro mixture.

Suitable protecting groups for the hydroxyl moieties of 3,4-dihydroxy benzaldehyde are ethers (e.g. benzyl and methyl) or cyclic acetals (e.g. methylene acetal). The removal of cyclic acetals or methyl ethers requires treatment with a Lewis acid (e.g. AlCl3) and a thiol (e.g. ethanethiol, a volatile compound with an extremely repulsive smell). To the contrary, the removal of benzyl ethers can be accomplished by simple, clean and quantitative hydrogenolysis.
The diastereomerically enriched mixture of the protected threo-DOPS can be converted into the optically active D- and L-threo-DOPS by optically resolving a racemic mixture of threo-2-(3,4-methylenedioxyphenyl)-N-carbobenzyloxyserine or threo-2-(3,4-dibenzyloxy-phenyl)-N-carbobenzyloxyserine, as detailed in U.S. Pat. Nos. 4,319,040 and 4,480,109, respectively. Following optical resolution of these racemic mixtures to give the desired L-enantiomer, the methylenedioxy or benzyl groups must be removed from the catechol moiety and the carbobenzyloxy (Cbz) group must be removed from the amine group to give Droxidopa.
According to an alternative approach described in patent EP 201039 B1, a racemic mixture of threo-2-(3,4-dibenzyloxy-phenyl)-N-acetylserine can be converted into L-threo-2-(3,4-dibenzyloxy-phenyl)-serine by treatment with a L-amino acylase.
A disadvantage associated with all the synthetic pathways cited above is that in converting a racemic starting material using an enantioselective enzyme or an optically active amine, a maximum yield of 50% of the enantiomerically pure end product can be reached.
An alternative procedure for the stereoselective preparation of Droxidopa has been described in patent EP 375554 B1. According to the latter, the two stereocenters are introduced simultaneously with a Noyori-type asymmetric hydrogenation with dynamic kinetic resolution (AH-DKR). The process is particularly interesting because it is catalyzed by the cheapest of the transition metals (ruthenium) and of the chiral phosphines (Binap) employed in asymmetric hydrogenations. However the proposed conditions are not suitable for an industrial production of Droxidopa, because: 100 bar of hydrogen pressure is out of reach in normal industrial vessels; the reported reaction time is unpractical (almost 1 week); the best solvent is dichlorometane (which should be avoided for environmental concerns); and the deprotection of the methylenedioxy moiety requires large excesses of AlCl3 or AlBr3.
A stereoselective enzymatic approach to Droxidopa has been described in patent JP 5028850 and entails the coupling of glycine or a salt thereof with 3,4-dihydroxybenzaldehyde in the presence of a threonine aldolase to form the corresponding enantiomerically enriched amino acid derivative.
An innovative synthetic approach for the preparation of diastereomerically and enantiomerically enriched oxazolines (A) (by reaction of isocyanoacetates with aldehydes in the presence of 9-amino(9-deoxy)epi Cinchona alkaloid derivatives and a salt of silver or gold) has been described in the Journal of the American Chemical Society (2011), 133, 1710-1713.

Said oxazolines (A) can be further converted into the corresponding tert-butyl esters by hydrolysis.
Aim of this invention is to provide a chemical method to prepare Droxidopa or intermediates useful in the synthesis thereof, characterized by high yields and levels of stereocontrol avoiding the use of dangerous reagents and providing the desired compounds with a purity appropriate for the use in pharmaceuticals.